The discovery of tumor specific antigens (neoantigens) that arise during tumor development inspired Burnet's immune surveillance theory. This theory states that the immune system is able to recognize and eliminate newly developing tumors based on the presence of neoantigens. However, since then many experiments have shown that immunocompromised individuals do not develop more malignancies than normal immunocompetent individuals, thus contradicting the idea that the immune system plays a protective role against the development of cancer. Therefore, it appears that tumors and their specific antigens do not provoke any immune response.
This phenomenon can be explained by the “two signal model of lymphocyte activation” of Brestcher and Cohn (Brestscher, P. and M. Cohn, A theory of self-nonself discrimination, Science (1970) 169(950):1042). This model states that for full activation of a T cell, two signals must be provided. Signal one comes from the recognition of a specific antigen through engagement of the T cell receptor, and signal two is provided by costimulatory molecules present on the antigen-presenting cell (APC). In the absence of costimulation, the T cell will not elicit an immune response against the antigen. Rather, it will assume a state known as anergy (Jenkins, M. K., and Schwartz R. H., Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo, J Exp Med (1987) 165(2): p. 302-319), which will be maintained even if the antigen is provided again.
APCs remain in a resting state in the absence of danger signals that indicate the presence of a pathogen and/or tissue damage. In the resting state, the APCs express low levels of costimulatory molecules and cytokines that would otherwise cause T cell activation. This mechanism is known as peripheral tolerance and avoids the production of harmful immune responses against self-antigens. Only when “danger” is associated with antigen presentation would APCs mature to an “activating state”, leading to T cell priming. Recent studies suggest that although tumor antigens are presented by antigen presenting cells, the antigens are not effective in inducing maturation of the antigen presenting cells. As a result, the antigen presenting cells do not express sufficient costimulatory molecules, and the T cells engaged by such antigen presenting cells become tolerant to the antigen being presented.
Vaccination against cancer has been explored to eradicate tumor cells. In order for tumor cells to survive and proliferate, they must be able to avoid and/or overcome the immune system of the host. For example, induction of antigen specific CD4+ T cell tolerance is one of the mechanisms by which tumor cells overcome immune responses. Therefore, it is desirable to develop a vaccine that is capable of inhibiting tolerance or activating T cells that have escaped tolerance induction due to their low affinity for the tumor antigens.